EP2864295B1 - Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one et this1,2,4-tetrahydropyrimido {1,2-a}pyrimidin-6-one comprenant une morpholine substituee, leurs preparation et utilisation pharmaceutique - Google Patents

Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one et this1,2,4-tetrahydropyrimido {1,2-a}pyrimidin-6-one comprenant une morpholine substituee, leurs preparation et utilisation pharmaceutique Download PDF

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EP2864295B1
EP2864295B1 EP13773341.6A EP13773341A EP2864295B1 EP 2864295 B1 EP2864295 B1 EP 2864295B1 EP 13773341 A EP13773341 A EP 13773341A EP 2864295 B1 EP2864295 B1 EP 2864295B1
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pyrimidin
trifluoromethyl
tetrahydropyrimido
methylmorpholin
ylmethyl
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EP2864295A2 (fr
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Youssef El-Ahmad
Bruno Filoche-Romme
Jean-Philippe Letallec
Gilbert Marciniak
Baptiste Ronan
Bertrand Vivet
Maurice Brollo
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Sanofi SA
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Sanofi SA
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel 2,3-dihydro-1H-imidazo ⁇ 1,2-a ⁇ pyrimidin-5-one and 1,2,3,4-tetrahydropyrimido ⁇ 1,2-a ⁇ pyrimidin-6-one chemical compounds comprising a substituted morpholine, to pyrimidinone derivatives, to the process for preparing same, to the novel intermediates obtained, to the use thereof as medicaments, to the pharmaceutical compositions containing them and to the novel use of such derivatives.
  • the present invention thus also relates to the use of said derivatives for preparing a medicament intended for treating humans.
  • the invention relates to novel pyrimidinone derivatives and to the pharmaceutical use thereof for preventing and treating conditions capable of being modulated by inhibiting the Vps34/PIK3C3 pathway.
  • Vps34/PIK3C3 is a key contributor in autophagy.
  • Vps34/PIK3C3 is also involved in phenomena of vesicular trafficking such as endocytosis and phagocytosis ( B. Vanhaesebroeck et al. Nat Rev Mol Cell Biol 2010 ).
  • Vps34 also has a role in the signalling of the mTOR protein ( X. Zhou et al. Plos One 2011 , N. Jaber et al. PNAS 2011 , MS Yoon et al.
  • Vps34 has been shown to be involved in cell proliferation ( EE Johnson et al. J Cell Science 2005 , X. Zhou et al. Plos One 2011 , N. Jaber et al. PNAS 2012 ).
  • Vps34/PIK3C3 constitutes in particular a new mechanism of action for treating a large number of cancer diseases including solid and liquid tumours.
  • Vps34/PIK3C3 signalling pathway is a complex network which regulates multiple cell functions summarised under the name vesicular trafficking ( B. Vanhaesebroeck et al. Nat Rev Mol Cell Biol 2010 ).
  • This signalling pathway is an important target in the treatment of cancer, since vesicular trafficking phenomena such as autophagy, endocytosis and phagocytosis are modified in human tumours ( F. Janku et al. Nat Rev Clinical Oncol 2011 , Y. Mosesson Nat Rev Cancer 2008 ).
  • Vps34/PIK3C3 The class III PI3K lipid kinase (Vps34/PIK3C3) forms a heterodimer with the Vps15 protein.
  • Vps15 is a protein which is myristoylated, thus enabling the Vps34/Vps15 complex to be anchored in membranes. This heterodimer is found in various multiprotein complexes, thus underlining its various biological functions (B. Vanhaesebroeck et al. Nat Rev Mol Cell Biol 2010).
  • Vps34/PIK3C3 phosphorylates phosphatidylinositol (PI) on the position 3 of the inositol, so as to give phosphatidylinositol 3 phosphate (PI3P).
  • PI3P is a secondary messenger.
  • Myotubularin (MTM) phosphatase lipids dephosphorylate PI3P on position 3.
  • MTM Myotubularin
  • JUMPY JUMPY proteins
  • the PI3P formed by Vps34/PIK3C3 is a key secondary messenger in autophagosome formation by the recruitment of proteins such as WIPI, DFCP1 and Alfy (S. Tooze et al, Nat Cell Biol 2010).
  • the autophagosomes formed will then fuse with lysosomes, making it possible to degrade constituents of the cytoplasm (organelles, long-lived proteins, etc.) (Z Yang et al. Nat Cell Biol 2010).
  • Autophagy is a mechanism of cell survival which enables the cell to survive in a situation of stress, for instance faced with a metabolic stress.
  • autophagy is implicated in the resistance of tumour cells faced with environmental stresses, such as: hypoxia, oxidative stresses, nutrient deficiency, but also faced with therapeutic stresses: treatments with anticancer agents, ionizing radiation.
  • this signalling pathway is a major factor of resistance to chemotherapy, to radiotherapy and to targeted therapies such as inhibitors of EGFR, HER2 or Bcr-Abl for example ( QW. Fan et al., Since signaling 2010 , A. Gupta et al. PNAS 2010 , X Li et al. Cancer Res 2010 , A Vazquez-Martin et al. PLos One 2009 , Z. Wu et al. Genes Cancer 2010 ).
  • Vps34/PIK3C3 protein has been described as being involved in the endosomal trafficking of certain transmembrane receptors such as receptor tyrosine kinases (EGF receptor, PDGF receptor) or the transferrin receptor, for example ( B. Vanhaesebroeck et al. Nat Rev Mol Cell Biol 2010 ).
  • Vps34 via the regulation of endosomes, has been shown to participate in the cytokinesis phenomenon during cell division ( AP Sagona et al. Nat Cell Biol 2010 ).
  • PI3P is also generated at the membranes of phagosomes.
  • the role of the Vps34/PIK3C3 protein does not appear to be involved in phagosome membrane initiation, but in phagosome maturation.
  • the PI3P formed by the Vps34/PIK3C3 protein is thought to be involved in the activation of NADPH oxidase at the phagosome level ( B. Vanhaesebroeck et al. Nat Rev Mol Cell Biol 2010 ).
  • Application WO2008/064244 describes the application of the PI3K ⁇ -inhibiting products TGX-221 and TGX-155 which are of use in the treatment of cancer, and in particular in breast cancer. These products are pyrido[1,2-a]pyrimidin-4-ones previously described in applications WO2004/016607 and WO2001 /053266 , which differ from the products of the present invention owing to their entirely aromatic nature and to their substitutions.
  • WO2011/001112 and WO2011/001113 disclose dihydroimidazo- or tetrahydropyrimido-pyrimidinone derivatives substituted on position 2 with an unsubstituted morpholin-1-yl group, as PI3K inhibitors.
  • R2 and R3 which may be identical or different, are such that R2 is a hydrogen atom or an alkyl radical optionally substituted with one or more fluorine atoms and R3 is an alkyl radical optionally substituted with one or more fluorine atoms, it being understood that R2 and R3 are not both CF 3 ; or else R2 and R3 form, together with the carbon atom to which they are bonded, a cyclic radical as defined above.
  • a subject of the present invention is the products of formula (I) as defined above, in which the morpholine residue is chosen from the following radicals: the radicals p, q, R1, R2, R3 and R4 having the meanings indicated above, said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • a subject of the present invention is thus the products of formula (I) as defined above, in which p is the integer 0 and q is the integer 2 or else p is the integer 2 and q is the integer 0; the radicals R1, R2, R3 and R4 and the morpholine residue having the meanings indicated above, said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • a subject of the present invention is thus the products of formula (I) as defined above, in which p is the integer 0 and q is the integer 1 or else p is the integer 1 and q is the integer 0; the radicals R1, R2, R3 and R4 and the morpholine residue having the meanings indicated above, said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • the products of formula (I) according to the present invention are thus the products of formula (I) as defined above, in which p is the integer 0 and q is the integer 1 or else p is the integer 1 and q is the integer 0; the radicals R1, R2, R3 and R4 and the morpholine residue having the meanings indicated above, said products of formula (I) being in any of the possible racemic, enantiomeric and diastereois
  • heteroaryl or bicyclic radicals mention may be made more particularly of pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl, benzothiazolyl or benzimidazolyl radicals optionally substituted with one or more substituents, which may be identical or different, as indicated above.
  • the carboxy radical(s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which mention may be made, for example, of:
  • the compounds of formula (I) can exist in the salt form, such salts being part of the invention; these salts can be prepared with pharmaceutically acceptable acids or bases ( P. Stahl, C. Wermuth; Handbook of pharmaceutical salts; Wiley Ed .), but other salts, obtained, for example, for the purification or isolation of the compounds of formula (I), are part of the invention.
  • the compounds of formula (I) can comprise one or more asymmetric centres. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and also mixtures thereof, including racemic mixtures, are part of the invention.
  • stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same structural formula, but the various groups of which are arranged differently in space, such as, in particular, in monosubstituted cyclohexanes, the substituent of which can be in the axial or equatorial position, and the various possible rotational conformations of ethane derivatives.
  • stereoisomerism owing to the different spatial arrangements of substituents attached either on double bonds or on rings, which is often referred to as geometric isomerism or cis-trans isomerism.
  • stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • R1 is an optionally substituted phenyl or pyridyl radical
  • R1 is a phenyl or pyridyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine and chlorine atoms and cycloalkyl, alkyl and alkoxy radicals, the latter alkyl and alkoxy radicals being themselves optionally substituted with one or more fluorine atoms, the other substituents R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, p and q of said products of formula (I) having the meanings indicated above.
  • R1 is a -(CH2) m -Ra radical
  • m is the integer 1 or 2 and in particular Ra is a radical -CO-Rb
  • -C(cycloalkyl) N-ORc
  • CO 2 Rd -CONRxRy a -CO-cyclopropyl, -CO-cyclobutyl, -CO-cyclopentyl or -CO-cyclohexyl radical, all optionally substituted with one or more alkyl radicals
  • such an aminated ring can be chosen in particular from piperidyl, morpholinyl, homomorpholinyl, azetidine, oxaazaspiro[3.3]heptane, isoxazolidine, ⁇ 1,2 ⁇ oxazinane, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, azepinyl, piperazinyl or homopiperazinyl radicals, these radicals being themselves optionally substituted as indicated above or hereinafter.
  • NRxRy forms a ring as defined above
  • such an aminated ring can be chosen in particular from piperidyl, morpholinyl, azetidine, oxaazaspiro[3.3]heptane, isoxazolidine or ⁇ 1,2 ⁇ oxazinane radicals.
  • R1 when R1 is the SO 2 Rb radical, then R1 is in particular the -SO 2 -phenyl radical optionally substituted with an alkyl radical or a halogen atom, the other substituents R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, p and q of said products of formula (I) having the meanings indicated above.
  • R1 is an alkyl radical
  • R1 is an alkyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms and hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, alkoxy, phenyl and pyridine radicals, the latter three radicals all being optionally substituted with one or more fluorine atoms, the other substituents R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, p and q of said products of formula (I) having the meanings indicated above.
  • R1 when R1 is a cycloalkyl radical, then R1 is in particular a cyclobutyl, cyclopentyl or cyclohexyl radical, the other substituents R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, p and q of said products of formula (I) having the meanings indicated above.
  • R1 when R1 is a heterocycloalkyl radical, then R1 is in particular an oxetane, tetrahydrofuran or tetrahydropyran radical, the other substituents R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, p and q of said products of formula (I) having the meanings indicated above.
  • R2 and R3 may be such that R2 is a hydrogen atom and R3 is the trifluoromethyl radical CF 3 , the other substituents R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, p and q of said products of formula (I) having the meanings indicated above.
  • R2 and R3 may be such that R2 is a methyl radical and R3 is the trifluoromethyl radical CF 3 , the other substituents R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, p and q of said products of formula (I) having the meanings indicated above.
  • R2 and R3 may be such that R2 and R3 are both a methyl radical, the other substituents R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, p and q of said products of formula (I) having the meanings indicated above.
  • one or more of the hydrogen atoms that R4, R5, R6, R7, R8, R9, R10, R11 and R12 of said products of formula (I) may represent can be a deuterium atom.
  • the cyclic radical that R2 and R3 may optionally form with the carbon atom to which they are bonded, as defined above can thus be a carbocyclic (spirocycloalkyl) radical such as the spirocyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, or else be a heterocyclic radical such as, for example, the oxetane radical, all these radicals being optionally substituted as defined above.
  • spirocycloalkyl such as the spirocyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical
  • a heterocyclic radical such as, for example, the oxetane radical
  • NRxRy forms a ring as defined above
  • such an aminated ring can be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl, homomorpholinyl, piperazinyl or homopiperazinyl radicals, these radicals being themselves optionally substituted as indicated above or hereinafter.
  • a subject of the present invention is the products of formula (I) as defined above, in which:
  • a subject of the present invention is thus the products of formula (I) as defined above, in which the morpholine residue is chosen from the following radicals: the other substituents R1, R2, R3, R4, p and q of said products of formula (I) having the meanings indicated above, said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • a subject of the present invention is thus the products of formula (I) as defined above, in which the morpholine residue is chosen from the following radicals: the other substituents R1, R2, R3, R4, p and q of said products of formula (I) having the meanings indicated above, said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • Rb can in particular be one of the following radicals as defined above: alkyl, such as, for example, methyl, ethyl or isopropyl; phenyl, pyridyl, thiazole, isoxazole, oxazole and oxadiazole; all optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine and chlorine halogen atoms and cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, piperidyl, morpholinyle, phenyl, pyridyl, alkyl and alkoxy radicals, the latter phenyl, pyridyl, alkyl and alkoxy radicals being themselves optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms and hydroxyl, alkyl and alkoxy radicals.
  • alkyl such as, for example, methyl, e
  • Rd can be an alkyl or cyclopentyl radical.
  • R4 can be a hydrogen atom or a fluorine atom.
  • R1 is a -(CH 2 ) m -Ra radical with m being the integer 1 or 2 and Ra being -CO-cycloalkyl or -CO-heterocycloalkyl
  • these cycloalkyl and heterocycloalkyl radicals are chosen, for example, from cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, piperidyl, tetrahydrofuran, tetrahydropyran and pyrrolidine radicals, all optionally substituted with one or more alkyl radicals and, in addition, optionally with CO 2 alk on the nitrogen of the pyrrolidine.
  • R1 when R1 is a -(CH 2 ) m -Ra radical with m being the integer 1 or 2 and Ra being -CO-Rb, then Rb can be, for example, an alkyl radical such as, in particular, methyl, ethyl, propyl, butyl or pentyl, all linear or branched, such as, for example isopropyl, tert -butyl, linear or branched butyl, linear or branched pentyl, which are optionally substituted as indicated above.
  • an alkyl radical such as, in particular, methyl, ethyl, propyl, butyl or pentyl, all linear or branched, such as, for example isopropyl, tert -butyl, linear or branched butyl, linear or branched pentyl, which are optionally substituted as indicated above.
  • a subject of the present invention is most particularly the products of formula (I) as defined above, corresponding to the following formulae:
  • a subject of the present application is also any process for preparing the products of formula (I) as defined above.
  • the products according to the invention can be prepared using conventional organic chemistry methods.
  • a subject of the present invention is thus in particular a process for synthesis of the products of formula (I) as defined above, described in scheme 1 or scheme 2.
  • Scheme 1 illustrates the methods used for preparing the products of formula (I). In this respect, they could not constitute a limitation of the scope of the invention, with regard to the methods for preparing the compounds claimed.
  • a subject of the present invention is thus also the process for preparing products of formula (I) according to scheme 1 as defined hereinafter.
  • a subject of the present invention is thus also the process for preparing products of formula (I) according to scheme 2 as defined hereinafter.
  • the intermediate L can be prepared according to the following scheme under the conditions indicated hereinafter: in which the substituents R2 and R3 have the meanings indicated above for the products of formula (I). in which the substituents n, p, q, PG, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and alkyl have the meanings indicated above for the products of formula (I). in which the substituents n, p, q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 have the meanings indicated above for the products of formula (I).
  • the diamines A are either commercially available, or prepared, in the achiral, chiral or racemic version, according to the methods known to those skilled in the art, such as, in particular, by analogy and homologation with the process described by Brigaud, T. et al. in J. Org. Chem. 2006, 71(18), 7075-7078 , for the values of n, R2 and R3 as defined above.
  • an amine such as aqueous ammonia
  • the diamines G can be obtained in particular by means of a reductive amination reaction of the commercially available diamines A via a conventional method as described, for example, by Larock, Richard, C. et al. in Comprehensive Organic Transformations A Guide to Functional Group Preparations from VCH and by Theodora W. Greene and Peter G. M. Wuts in Protective Groups in Organic Synthesis Third Edition from Wiley-Interscience , for the values of R2, R3, PG and n as defined above.
  • the guanidines B can be obtained in particular by reacting a diamine A and cyanogen bromide in a solvent such as water or acetonitrile, at a temperature between 0°C and the boiling point of the solvent, according to the conditions described, for example, by Gallet, T. et al. (EP1340761 2003 ) and Bacque, Eric et al. (WO2011001112A1 and WO2011001113A2 ), for the values of n, R2 and R3 as defined above.
  • a solvent such as water or acetonitrile
  • the guanidines B can be obtained by deprotection of the guanidines H according to the conventional methods known to those skilled in the art as described, for example, by Theodora W. Greene and Peter G. M. Wuts in Protective Groups in Organic Synthesis Third Edition from Wiley-Interscience, for the values of n, R2, R3 and PG as defined above.
  • the guanidines H can be obtained in particular by reacting a diamine G and cyanogen bromide in a solvent such as water or acetonitrile, at a temperature between 0°C and the boiling point of the solvent, according to the conditions described, for example, by Gallet, T. et al. (EP1340761 2003 ) and Bacque, Eric et al. (WO2011001112A1 and WO2011001113A2 ), for the values of n, R2, R3 and PG as defined above.
  • a solvent such as water or acetonitrile
  • the compounds E can be obtained in particular by condensation of the guanidines B with a dialkyl malonate (preferably dimethyl or diethyl malonate) D, in the presence of a base such as sodium methoxide, at a temperature between 0°C and 150°C, as described, for example, by Badawey E.-S.A.M. et al. (Eur J Med Chem, 1998, 33(5), 349-361 ) and Bacque, Eric et al. (WO2011001112A1 and WO2011001113A2 ), for the values of n, p, q, R2, R3 and R4 as defined above.
  • a dialkyl malonate preferably dimethyl or diethyl malonate
  • a base such as sodium methoxide
  • the compound E can be obtained by deprotection of the compound I according to the conventional methods known to those skilled in the art as described, for example, by Theodora W. Greene and Peter G. M. Wuts in Protective Groups in Organic Synthesis Third Edition from Wiley-Interscience , for the values of p, q, R2, R3, R4 and PG as defined above.
  • the compounds I can be obtained in particular by condensation of the guanidines H with a dialkyl malonate (preferably dimethyl or diethyl malonate) D, in the presence of a base such as sodium methoxide, at a temperature between 0°C and 150°C, as described, for example, by Badawey E.-S.A.M. et al. (Eur J Med Chem, 1998, 33(5), 349-361 ) and Bacque, Eric et al. (WO2011001112A1 and WO2011001113A2 ), for the values of n, p, q, R2, R3, R4 and PG as defined above.
  • a dialkyl malonate preferably dimethyl or diethyl malonate
  • a base such as sodium methoxide
  • the compounds F can be obtained in particular from the compounds E by treatment with a chlorinating agent such as phosphorus oxychloride, in the absence of solvent, at a temperature between 20°C and 150°C, or in the presence of a solvent such as dichloroethane, at a temperature between 20°C and the boiling point of the solvent, for instance under the conditions described by Yamashita, A. et al. (Syn. Commun. (2004), 34(5), 795-803 ) and Bacque, Eric et al. (WO2011001112A1 and WO2011001113A2 ), for the values of p, q, R2, R3 and R4 as defined above.
  • a chlorinating agent such as phosphorus oxychloride
  • a solvent such as dichloroethane
  • the compound F can be obtained by deprotection of the compound J according to the conventional methods known to those skilled in the art as described, for example, by Theodora W. Greene and Peter G. M. Wuts in Protective Groups in Organic Synthesis Third Edition from Wiley-Interscience , for the values of R2, R3, R4, p and q as defined above.
  • the compounds J can be obtained in particular from the compounds I by treatment with a chlorinating agent such as phosphorus oxychloride, in the absence of solvent, at a temperature between 20°C and 150°C, or in the presence of a solvent such as dichloroethane, at a temperature between 20°C and the boiling point of the solvent, for instance under the conditions described by Yamashita, A. et al. (Syn. Commun. (2004), 34(5), 795-803 ) and Bacque, Eric et al. (WO2011001112A1 and WO2011001113A2 ), for the values of p, q, R2, R3, R4 and PG as defined above.
  • a chlorinating agent such as phosphorus oxychloride
  • the compounds P can be obtained from the compounds F by reacting with a substituted morpholine, in the absence or in the presence of a solvent such as acetonitrile, at a temperature between 20°C and 200°C, in the presence or absence of a base such as triethylamine or sodium carbonate for example, by analogy as described, for example, by Aliabiev S.B. (Lett. Org. Chem. (2007), 4(4), 273-280 ) and Bacque, Eric et al. (WO2011001112A1 and WO2011001113A2 ), for the values of p, q, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 as defined above.
  • a solvent such as acetonitrile
  • the products of formulae (I) can be obtained from the compounds Q by reacting with a substituted morpholine, in the absence or in the presence of a solvent such as acetonitrile, at a temperature between 20°C and 200°C, in the presence or absence of a base such as triethylamine or sodium carbonate for example, by analogy as described, for example, by Aliabiev S.B. (Lett. Org. Chem. (2007), 4(4), 273-280 ) and Bacque, Eric et al. (WO2011001112A1 and WO2011001113A2 ), for the values of p, q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 as defined above.
  • a solvent such as acetonitrile
  • the amine group protected by PG may be, for example, a benzylamine, para-methoxybenzylamine, 2,4-dimethoxybenzylamine or 4-methoxyphenylethylamine.
  • the products of the present invention are in particular of use for antitumour therapies.
  • the products of the invention can thus also increase the therapeutic effects of commonly used antitumour agents.
  • the products of the invention can thus also increase the therapeutic effects of commonly used radiotherapies.
  • a subject of the invention is quite particularly, the products corresponding to the following formulae for use as medicaments:
  • the invention also relates to pharmaceutical compositions containing, as active ingredient, at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product and, where appropriate, a pharmaceutically acceptable carrier.
  • the invention also extends to the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above.
  • compositions of the present invention can also, where appropriate, contain active ingredients of other anti-mitotic medicaments, such as, in particular, those based on taxol, cisplatin, DNA-intercalating agents, and the like.
  • compositions can be administered orally, parenterally or locally by topical application to the skin and the mucous membranes or by intravenous or intramuscular injection.
  • compositions may be solid or liquid and be in any of the pharmaceutical forms commonly used in human medicine, for instance simple or sugar-coated tablets, pills, lozenges, gel capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods.
  • the active ingredient may be incorporated therein with excipients normally used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or nonaqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, or preservatives.
  • the usual dosage which is variable according to the product used, the individual treated and the condition in question, can be, for example, from 0.05 to 5 g per day in adults, or preferably from 0.1 to 2 g per day.
  • a subject of the present invention is also the use of products of formula (I) as defined above, for preparing a medicament intended for the treatment or prevention of a disease characterized by the dysregulation of the activity of a protein or lipid kinase.
  • Such a medicament can in particular be intended for the treatment or prevention of a disease in a mammal.
  • a subject of the present invention is in particular the use of a product of formula (I) as defined above, for preparing a medicament intended for the prevention or treatment of diseases associated with an uncontrolled proliferation.
  • a subject of the present invention is thus quite particularly the use of a product of formula (I) as defined above, for preparing a medicament intended for the treatment or prevention of diseases in oncology, and in particular intended for the treatment of cancers.
  • a subject of the present invention is the products of formula (I) as defined above, for use thereof in the treatment of solid or liquid tumours.
  • the cited products of the present invention can in particular be used for the treatment of primary tumours and/or of metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate, endometrial and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid haematopoietic tumours, in sarcomas, in brain, larynx and lymphatic system cancers, bone and pancreatic cancers, and in hamartomas.
  • gastric gastric, hepatic, renal, ovarian, colon, prostate, endometrial and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid haematopoietic tumours, in sarcomas, in brain, larynx and lymphatic system cancers, bone and pancreatic
  • a subject of the present invention is also the use of the products of formula (I) as defined above, for preparing medicaments intended for cancer chemotherapy.
  • a subject of the present invention is therefore the products of formula (I) as defined above, for use thereof in cancer chemotherapy, alone or in combination.
  • the products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or else in combination, for example, with other therapeutic agents.
  • Such therapeutic agents may be commonly used antitumour agents.
  • a therapeutic benefit can in particular be expected when administering the products of the present application in combinations with varied targeted therapies.
  • targeted therapies are in particular the following: i) targeted therapies which inhibit kinases or pseudo-kinases such as EGFR, HER2, HER3, PI3K, AKT, mTOR, Bcr-Abl, Kit, PDGFR or Src ( QW. Fan et al., Since signaling 2010 , A. Gupta et al. PNAS 2010 , X Li et al. Cancer Res 2010 , A Vazquez-Martin et al. PLos One 2009 , Z. Wu et al.
  • Genes Cancer 2010 ii) targeted therapies which inhibit the oestrogen receptor, the proteasome, the HDAC protein ( JS Samaddar et al. Mol Cancer Ther 2008 , B; Hoang et al. Mol Cancer Ther 2009 , JS Carew et al. Blood 2007 ).
  • a therapeutic effect can also be expected when combining the products of the present application with chemotherapy agents such as camptothecin, taxotere or 5-FU, for example; or else when combining them with radiotherapy ( J Li et al. Eur J of Cancer 2010 , A. Appel et al. Cancer Res 2008 ).
  • a subject of the present invention is in particular the use of a product of formula (I) as defined above, for preparing a medicament intended for the prevention or treatment of lysosomal diseases such as glycogenosis type II (or Pompe's disease) or Danon disease, for example ( N. Raben et al., Autophagy 2010 , B Levine et al. Cell 2008 , N. Mizushima et al. Nature 2008 ).
  • lysosomal diseases such as glycogenosis type II (or Pompe's disease) or Danon disease, for example ( N. Raben et al., Autophagy 2010 , B Levine et al. Cell 2008 , N. Mizushima et al. Nature 2008 ).
  • Such medicaments intended for the treatment of lysosomal diseases can be used alone or in combination, for example, with other therapeutic agents.
  • a subject of the present invention is also the use of a product of formula (I) as defined above, for preparing a medicament intended for the prevention or treatment of X-linked myotubular myopathies, Charcot-Marie-Tooth disease; where mutations of the proteins of the myotubularin family have been described ( I. Vergne et al., FEBS Lett, 2010 ).
  • a subject of the present invention is thus the use as defined above, in which said products of formula (I) are alone or in combination.
  • cancers the treatment of solid or liquid tumours, and the treatment of cancers resistant to cytotoxic agents are of interest.
  • the products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or else in combination, for example, with other therapeutic agents.
  • Such therapeutic agents may be commonly used antitumour agents.
  • kinase inhibitors mention may be made of butyrolactone, flavopiridol, 2(2-hydroxyethylamino)-6-benzylamino-9-methylpurine known as olomucine, sorafenib, imatinib, erlotinib, gefitinib and lapatinib.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof as a VPS34 inhibitor.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of cancers.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of solid or liquid tumours.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of cancers resistant to cytotoxic agents.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of primary tumours and/or of metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid haematopoietic tumours, in sarcomas, in brain, larynx and lymphatic system cancers, bone and pancreatic cancers, and in hamartomas.
  • gastric gastric, hepatic, renal, ovarian, colon, prostate and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid haematopoietic tumours, in sarcomas, in brain, larynx and lymphatic system cancers, bone and pancreatic cancer
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in cancer chemotherapy.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in cancer chemotherapy, alone or in combination.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of lysosomal diseases such as glycogenosis type II (or Pompe's disease) or Danon disease.
  • lysosomal diseases such as glycogenosis type II (or Pompe's disease) or Danon disease.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of X-linked myotubular myopathies and Charcot-Marie-Tooth disease.
  • a subject of the present invention is also, as novel industrial products, 5 certain starting products or synthesis intermediates of formulae A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, T1, T2 and T3 as defined above.
  • the intermediates P are an object of the invention.
  • the microwave oven used is a Biotage, InitiatorT'VI Eight, 400W max, 2450 MHz apparatus.
  • the 1 H NMR spectra at 400 MHz and 1 H NMR spectra at 500 MHz were carried out on a Bruker Avance 250 or Bruker Avance DRX-400 or Bruker Avance DPX-500 spectrometer with the chemical shifts ( ⁇ in ppm) in the solvent dimethyl sulfoxide-d 6 (DMSO-d 6 ) referenced at 2.5 ppm at the temperature of 303K.
  • DMSO-d 6 solvent dimethyl sulfoxide-d 6
  • MS mass spectra
  • optical rotations were measured on a model 341 polarimeter from Perkin Elmer. Wavelength: sodium ⁇ line (589 nm).
  • the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 0.9 g of the solid S2.
  • the solid S1 is taken up with water and ethyl acetate. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 3.5 g of the solid S3.
  • 1-(2,4-Dimethoxybenzyl)-4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine can be prepared in the following way.
  • N1-(2,4-Dimethoxybenzyl)-4,4,4-trifluorobutane-1,3-diamine can be prepared in the following way.
  • 3-Amino-N-(2,4-dimethoxybenzyl)-4,4,4-trifluorobutyramide can be prepared in the following way.
  • 23.4 g of 2,4-dimethoxybenzylamine are added in one step to a suspension of 20 g of 3-amino-4-trifluorobutyric acid in 120 ml of DMF, followed, dropwise, by 41 g of phenylsilane, said additions being carried out while maintaining the temperature of the reaction medium between 20 and 28°C.
  • the reaction medium a suspension, is stirred at ambient temperature for 48 hours.
  • the reaction medium is cooled to 4°C in an ice bath, and then 200 ml of water, followed by 300 ml of ethyl acetate, are added dropwise.
  • the resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the reaction medium is concentrated to dryness under reduced pressure.
  • the mixture is concentrated to dryness under reduced pressure.
  • the residue obtained is taken up with an 80/20 dichloromethane/MeOH mixture and filtered, and then the filtrate is concentrated to dryness under reduced pressure.
  • (8S)-2-Chloro-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one and (8R)-2-chloro-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.
  • the aqueous phase is extracted with 20 ml of ethyl acetate.
  • the organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated to dryness under reduced pressure (2.7 kPa).
  • the crude obtained is purified by flash chromatography on silica [eluent: dichloromethane/1-propanol/acetonitrile (100/0/0 then 96/2/2 by volume)].
  • reaction medium is stirred in the cold bath for approximately 15 minutes and then, after having added approximately 3 ml of ethyl ether to the reaction medium, the latter is filtered through a sintered glass funnel. After drying under vacuum, 92 mg of 2-hydroxy-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a beige solid.
  • 2-Methyl-2-(trifluoromethyl)butane-1,4-diamine can be prepared in the following way.
  • the aqueous phase is extracted with ethyl ether, then the organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated in a rotary evaporator under reduced pressure (the bath temperature is maintained below 25°C and the pump vacuum is maintained above 100 mbar). 469 mg of 2-methyl-2-(trifluoromethyl)butane-1,4-diamine are obtained, in the form of a yellow liquid.
  • N 1 -benzyl-4,4,4-trifluoro-3-methylbutane-1,3-diamine can be prepared in the following way.
  • the reaction medium is stirred at ambient temperature for 72 h and is then diluted with 80 ml of ethyl ether and 15 ml of THF and cooled to approximately 0°C, and 2.18 ml of water, 2.18 ml of an aqueous 15% sodium hydroxide solution and 6.54 ml of water are successively added slowly, and the mixture is filtered through a sintered glass funnel.
  • the filtrate is dried over magnesium sulfate and then, after filtration through a sintered glass funnel, the filtrate obtained is evaporated to dryness under reduced pressure (2.7 kPa).
  • 3-Amino-N-benzyl-4,4,4-trifluoro-3-methylbutanamide can be prepared in the following way.
  • the reaction medium is stirred at ambient temperature for 62 h and then 3.26 ml (29.86 mmol) of benylamine are added.
  • the reaction medium is stirred at ambient temperature for 27 h and then evaporated to dryness under reduced pressure (2.7 kPa).
  • the crude obtained is purified by flash chromatography on silica [eluent: dichloromethane/1-propanol/acetonitrile (96/2/2 then 90/5/5 by volume)]. After evaporation of the fractions under reduced pressure, 2.504 g of 3-amino-N-benzyl-4,4,4-trifluoro-3-methylbutanamide are obtained, in the form of a brown oil.
  • 3-Amino-4,4,4-trifluoro-3-methylbutanoic acid hydrochloride can be prepared in the following way.
  • Ethyl 3-amino-4,4,4-trifluoro-3-methylbutanoate and methyl 3-amino-4,4,4-trifluoro-3-methylbutanoate can be prepared in the following way.
  • a mixture of 2 g of 4,4-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrobromide, 10 ml of ethyl malonate and 2.6 g of sodium methoxide is heated to 100°C. After 4 h of heating, the reaction medium is concentrated to dryness. The oil obtained is taken up in ethyl ether. The precipitate is filtered off and then the residue is taken up in 7 ml of water and acidified with 25% HCl to pH 6. The precipitate formed is filtered off, washed with ethyl ether and oven-dried under vacuum.
  • 4,4-Dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrobromide can be prepared in the following way.
  • 3-Methylbutane-1,3-diamine dihydrobromide can be prepared in the following way.
  • Ethyl (3-amino-1,1-dimethylpropyl)carbamate can be prepared in the following way.
  • Ethyl [3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1,1-dimethylpropyl]carbamate can be prepared in the following way.
  • 2-(3-Methylbut-2-en-1-yl)-1H-isoindole-1,3-dione can be prepared in the following way.
  • a suspension of 5 g of 4,4-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine, 29 g of dimethyl fluoromalonate and 3.9 g of sodium methoxide is heated at 100°C for 3 hours.
  • the reaction medium is concentrated to dryness under reduced pressure.
  • the residue obtained is taken up with ethyl ether.
  • the solid formed is filtered off and then dried. 10 ml of water are added to the solid obtained, and the resulting mixture is cooled on ice, before acidification to pH 5-6 by adding concentrated hydrochloric acid (25%).
  • a mixture of 7 g of (2R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol in 40.5 ml of methanol, 23.5 ml of 3N hydrochloric acid and 0.94 g of Pd(OH) 2 /C (20%) is hydrogenated at 22°C in an autoclave, under a hydrogen pressure of 5 bar, for 18 hours.
  • the mixture obtained is then filtered and the filtrate is evaporated to dryness.
  • the oil obtained is taken up with a 3N hydrochloric acid solution (50 ml).
  • the mixture obtained is extracted with diethyl ether (3 x 50 ml).
  • (2R)-2-((S)-1-Aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol can be prepared in the following way.
  • (2S)-3,3,3-Trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile can be prepared in the following way.
  • the solution is cooled to -20°C in a dry ice/isopropanol bath.
  • Ethylmagnesium bromide (amount and number of equivalents indicated in the table of the Examples) is added. After 10 minutes of stirring at -20°C, the cooling bath is withdrawn and the reaction mixture is stirred at ambient temperature for 3 hours. 5 ml of a saturated NH 4 Cl solution and 10 ml of EtOAc are added. After separation by settling out, the organic phase is dried over MgSO 4 , filtered, and then concentrated under reduced pressure. The expected compound is isolated.
  • the reaction mixture is cold-hydrolysed by adding saturated NH 4 Cl solution, extracted with EtOAc, dried over MgSO 4 , filtered and evaporated.
  • the compound obtained is purified on a 12 g Varian silica column, elution being carried out with 8 CH 2 Cl 2 /2 solution B (38 CH 2 Cl 2 /17 MeOH/2 20% NH 4 OH), at a flow rate of 40 ml/min with manual collection.
  • the fractions containing the product are concentrated under reduced pressure.
  • the expected compounds are isolated (see table of the Examples).
  • the reaction mixture is cold-hydrolysed by adding saturated NH 4 Cl solution, extracted with EtOAc, dried over MgSO 4 , filtered and evaporated.
  • the compound is purified on chiral phase (Example-70, Chiral Purif ref., see Examples table) or else on a 12 g silica column, elution being carried out with 8 CH 2 Cl 2 /2 solution B (38 CH 2 Cl 2 /17 MeOH/2 20% NH 4 OH at a flow rate of 40 ml/min with manual collection.
  • the fractions containing the product are concentrated under reduced pressure.
  • the expected compounds are isolated (see table of the Examples) (Example-61, 63, 67, 68).
  • Method-48 The alkyl carboxylate derivative is placed in solution in methanol and then treated with a sodium hydroxide solution until the ester has disappeared. Subsequent acid-base treatment makes it possible to isolate the acid intermediate which is used in the subsequent step.
  • Method-49 The intermediate obtained via the previous reaction (1 eq) is placed in solution in dioxane and a solution of hydrochloric acid in dioxane (4M, 10 eq) is added to the reaction mixture. The reaction mixture is stirred at 20°C until the protective group has been eliminated. The reaction mixture is poured into water, separated by settling out, and extracted with ethyl acetate.
  • the compound obtained is chromatographed on a 15 g (15-40 ⁇ m) Merck column at a flow rate of 20 ml/min, elution being carried out with isopropyl ether (1 min) and then isopropyl ether/MeOH at 99/01 (2 min), 98/02 (2 min), 95/05 (5 min) and 90/10 (for 10 min).
  • the fractions containing the fluorination compound (Example-266) and also the elimination compound (Example-267) are brought to dryness in a rotary evaporator.
  • Method-51 The intermediate obtained by the previous reaction (1 eq, 150 mg) is treated with hydrazine hydrate (number of equivalents, see table of the Examples) in the presence of acetic acid at 90°C for 2 h. After returning to 20°C, the reaction mixture is brought to dryness; a white solid is obtained, water is added, filtration is carried out, and washing is carried out with a 10% sodium bicarbonate solution and twice with water, drying is carried out under vacuum for 1 h, then washing is carried out with diisopropyl ether, rinsing is carried out once and twice with pentane, and drying is carried out under vacuum overnight. The expected compound is isolated.
  • Method-52 The carbonylated derivative is placed in solution in cold methanol, and then sodium borohydride (3 eq) is added. The progression of the reduction is monitored by TLC. After treatment, the mixture of the two diastereoisomers is obtained, which is separated by chiral-phase chromatography (Example-286 & Example-287) or which is kept as it is and which is used in the next step (see Examples table).
  • Method-53 The hydroxylated derivative is placed in solution in THF at 20°C, then treated with sodium hydride (4 eq). After 30 min at ambient temperature, iodomethane (4 eq) is added.
  • Example-288 & Example-289 see Examples table.
  • Method-54 In a 25 ml three-necked reactor, the synthesis intermediate previously obtained (number of equivalents, see table of the Examples) is introduced into ethanol and then palladium (number of equivalents, see table of the Examples) is added. The reaction medium is heated to 65°C and then hydrazine hydrate (number of equivalents, see table of the Examples) is added dropwise. The mixture is kept at this temperature for 30 minutes.
  • the expected compound is isolated and is used in the next step.
  • Method-57 The intermediate obtained during the previous reaction (1 eq) is placed in solution in dichloromethane and then stirred for 3 h at 20°C. The reaction mixture is poured into a saturated NaHCO 3 solution, separated by settling out and extracted with dichloromethane, and then washed with an Na 2 S 2 O 3 solution. The organic extracts are dried over magnesium sulphate, filtered and evaporated. The expected compound is obtained and is used in the next step.
  • Method-58 The carboxylated intermediate is placed in solution in DMF in the presence of 2.2 eq of the amino derivative to be coupled (see table reference), of hydroxybenzotriazole (2.4 eq), of EDCI (2.4 eq) and of DIPEA (6 eq). The reaction mixture is stirred at 20°C. After treatment, the caboxyamide derivative is isolated.
  • Method-59 The intermediate obtained during the previous reaction (1 eq) is placed in solution in ethanol in the presence of hydroxylamine hydrochloride (3 eq) and of triethylamine, and then stirred at 60°C.
  • Chiral purification -23 Method-60 The intermediate obtained during the previous reaction (1 eq) is placed in solution in pyridine in the presence of O-methylhydroxyamine hydrochloride (4 eq) and of triethylamine, and then stirred at 100°C for 4 h.
  • Chiral purification -24 Method-61 The intermediate obtained during the previous reaction (1 eq) is treated with trimethylsulphoxonium iodide (4 eq) suspended in a mixture of tBuOH (15 ml) and tBuOK (4 eq) at 50°C for 48 h.
  • Reagent-2 Thiazol-2-ylmethyl paratoluenesulphonate 1 eq of thiazol-2-ylmethanol [358-87-1] is treated with 1.5 eq of tosyl chloride [98-59-9] in the presence of 2 eq of TEA [121-44-8] in CH 2 Cl 2 at 0°C, and then the mixture is allowed to return to 20°C for 1 h at AT. After treatment, the compound is used as it is in the next step.
  • Reagent-3 (s)-2-Methoxy-2-phenyl-ethylene paratoluenesulphonate (ref. Reagent-3 table)
  • S paratoluenesulphonic acid chloride (1.5 g) in the presence of TEA in dichloromethane at 0°C, and then the mixture is stirred for one hour at 20°C. After treatment, the compound obtained is used as it is in the next reaction.
  • Reagent-4 (2S)-1-(2-Hydroxy-3-methylbutyl)-8-((R)-3-methylmorpholino)-2-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one
  • the NaBH 4 -reduction compound of EX-03 is used without prior separation of the diastereoisomers.
  • Reagent-5 2-Bromo-1-(5-methylisoxazol-3-yl)ethanone
  • the 2-bromo-1-(5-methylisoxazol-3-yl)ethanone is obtained according to the procedure described in J. Med. Chem.,1991, 34, 600-605 .
  • Reagent-6 2-Bromo-1-(4-methyltetrahydro-2H-pyran-4-yl)ethanone
  • the 2-bromo-1-(4-methyltetrahydro-2H-pyran-4-yl)ethanone is prepared by bromination of 1-(4-methyltetrahydro-2H-pyran-4-yl)-ethanone in methanol (1:1) at 0°C.
  • Reagent-7 1-(4-Methyltetrahydro-2H-pyran-4-yl)ethanone
  • the 1-(4-methyltetrahydro-2H-pyran-4-yl)ethanone is prepared by reacting methyl magnesium bromide (3M, ethyl ether, 64 mmol) with the N-methoxy-N,4-dimethyltetrahydro-2H-pyran-4-carboxamide derivative (32 mmol) in THF (100 ml). Addition at 0°C and return to 20°C over a period of 16 hours.
  • N-methoxy-N,4-dimethyltetrahydro-2H-pyran-4-carboxamide is obtained from 4-methyltetrahydro-2H-pyran-4-carboxylic acid (34 mmol) by coupling with N,O-dimethylhydroxylamine hydrochloride (35 mmol) in the presence of DMAP (35 mmol), EDCI (35 mmol) and N-methylmorpholine (35 mmol) in 75 ml of dichloromethane.
  • 2-cyclopropyl-2-fluoroethyl 4-methylbenzene-sulphonate is prepared from a solution of 2-cyclopropyl-2-fluoroethanol (532 mg, 5.11 mmol) (prepared as in Bioorganic and Medicinal Chemistry Letters 2011, Vol. 21, 276-279 ) and p-toluenesulphonyl chloride (1.25 g, 6.49 mmol) in dichloromethane (15 ml) which is cooled to -10°C in an ice/acetone bath and then treated with triethylamine (907.72 ⁇ l, 6.49 mmol).
  • Tablets corresponding to the following formula were prepared: Product of Example 42 0.2 g Excipient for a tablet with a final weight of 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).
  • Example 42 is taken by way of example of a pharmaceutical preparation, it being possible for this preparation to be carried out, if desired, with other products in examples in the present application.
  • This test is based on the detection of the ADP produced during the phosphorylation of PI by Vps34 in the presence of ATP.
  • the ADP is detected by TR-FRET (Time resolved - Fluorescence Resonance Energy transfer) using the Transcreener kit sold by Cisbio (HTRF® Transcreener® ADP, reference 62ADPPEB).
  • the molecules are diluted 3-fold in pure dimethyl sulfoxide (DMSO, Sigma Fluka 41647), and then diluted, in a second step, in 10% DMSO in water. 2 ⁇ l of molecules are added to 96-well plates (Corning Costar 3694), followed by 8 ⁇ l of a PI (Sigma P5766) / recombinant Vps34 (Invitrogen PV5126 or produced by Sanofi) mixture in buffer A: 50 mM Hepes, 5 mM MnCl 2 , 0.1% CHAPS, 2 mM TCEP, pH 7.1. The reaction is initiated with 10 ⁇ l of a solution of ATP (Sigma A7699) in buffer A and lasts 1 hour at ambient temperature.
  • a solution of ATP Sigma A7699
  • the concentrations during the reaction are 1% DMSO, 10 ⁇ M ATP, 55 ⁇ g/ml PI, approximately 3 nM of Vps34 and between 0.51 nM and 10 ⁇ M for the molecules.
  • the amount of enzyme is adapted to each batch so as to form approximately 2 ⁇ M of ADP during the reaction.
  • a range of ADP and of ATP for calibrating the results is prepared according to the indications of the kit.
  • Controls not containing enzyme (negative control) or not containing molecules (positive control) are also prepared in parallel.
  • the reaction is then blocked and visualised with the transcreener kit using 10 ⁇ l of each of the two reagents and according to the indications of the kit.
  • the fluorescence emission is detected on a Rubystar instrument at 620 and 665 nm.
  • the signal ratio is calculated by dividing the 665 nm signal by the 620 nm signal and then multiplying by 10 000.
  • the signal ratios are converted into ADP concentration using the calibration range and according to the instructions of the kit.
  • the percentages of inhibition by the molecules are calculated relative to the positive controls according to the formula (1 - signal ratio of the molecule/signal ratio of the positive control) x 100.
  • the absolute IC50s (inhibitory concentration which gives 50% inhibition) are calculated according to a 4-parameter logistical model. Two independent experiments make it possible to calculate the mean of the IC50s.
  • the IC50 results, in nM, obtained for the products in examples of the present invention are given in the table below.

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Claims (20)

  1. Produits de formule (I) :
    Figure imgb0407
     dans laquelle :
    p et q représentent les entiers 0, 1 ou 2 de sorte que, si p = 0, alors q = 1 ou 2 et, si p = 1 ou 2, alors q = 0 ;
    R1 est choisi parmi les valeurs suivantes a) à e) :
    a) R1 représente un radical phényle ou pyridyle éventuellement substitué par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes d'halogène et les radicaux cycloalkyle, alkyle et alkoxy, ces derniers radicaux alkyle et alkoxy étant eux-mêmes éventuellement substitués par un ou plusieurs atomes de fluor ;
    b) R1 représente un radical -(CH2)m-Ra, m représentant un entier 1 ou 2 et Ra un radical aryle ou hétéroaryle éventuellement substitué, ou un radical -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-Rb, -C(Rb)=N-ORc, -CO2Rd ou -CONRxRy ;
    c) R1 représente un radical alcényle ; un radical cycloalkyle ; un radical hétérocycloalkyle ; ou un radical alkyle éventuellement substitué par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et les radicaux hydroxyle, cycloalkyle, hétérocycloalkyle, phényle, pyridine et alkoxy, ces derniers radicaux phényle, pyridine et alkoxy étant eux-mêmes éventuellement substitués par un ou plusieurs atomes de fluor ;
    d) R1 représente un radical -SO2-Rb ;
    e) R1 représente un radical -CO-Re ;
    Rb représente un radical éventuellement substitué alkyle, cycloalkyle, aryle ou hétéroaryle ;
    Rc représente un atome d'hydrogène ou un radical alkyle ;
    Rd représente un radical alkyle ou cycloalkyle ;
    Re représente un radical éventuellement substitué alkyle, cycloalkyle, hétérocycloalkyle, aryle ou hétéroaryle ;
    NRxRy étant tel que Rx et Ry, qui peuvent être identiques ou différents, sont choisis parmi un atome d'hydrogène et les radicaux alkyle, cycloalkyle, alkoxy et phényle ; ou Rx et Ry forment, avec l'atome d'azote auquel ils sont liés, un radical cyclique comportant entre 3 et 7 chaînons ainsi qu'éventuellement un ou plusieurs autres hétéroatomes choisis parmi 0, NH et N-alkyle ;
    R2 et R3, qui peuvent être identiques ou différents, sont choisis parmi un atome d'hydrogène et un radical alkyle éventuellement substitué par un ou plusieurs atomes de fluor, étant entendu que R2 et R3 ne représentent pas tous deux CF3 et R2 et R3 ne représentent pas tous deux un atome d'hydrogène ; ou R2 et R3 forment, avec l'atome de carbone auquel ils sont liés, un radical cyclique comportant entre 3 et 6 chaînons ainsi qu'éventuellement un ou plusieurs autres hétéroatomes choisis parmi 0, S et -NRz, ce radical cyclique étant éventuellement substitué par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes d'halogène et les radicaux oxo, Rz, -ORz et -NRzRz' ; Rz et Rz', qui peuvent être identiques ou différents, représentant un atome d'hydrogène ou un radical alkyle, cycloalkyle ou hétérocycloalkyle ;
    R4 représente un atome d'hydrogène, de fluor ou de chlore, un radical méthyle ou un radical CN ;
    le résidu morpholine est substitué par les radicaux R5 à R12, qui peuvent être identiques ou différents, choisis parmi un atome d'hydrogène et des radicaux méthyle et éthyle éventuellement substitués par un atome de fluor ou un radical hydroxyle, étant entendu qu'au moins l'un des radicaux R5 à R12 ne représente pas un atome d'hydrogène ou ce résidu morpholine comporte un pont défini de la façon suivante : R7 ou R8 peut former un pont éthylène avec R9 ou R10, ou R7 ou R8 peut former un pont méthylène de configuration absolue R,R avec R11 ou R12, ou encore R5 ou R6 peut former un pont méthylène de configuration absolue R,R avec R9 ou R10 de sorte à obtenir les radicaux suivantes :
    Figure imgb0408
     et l'isomère de configuration R,R
    Figure imgb0409
    les radicaux aryle et hétéroaryle que peuvent représenter Ra, Rb et Re, ainsi que les radicaux alkyle que peuvent représenter Rb et Re étant éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes d'halogène et les radicaux cycloalkyle, hétérocycloalkyle, hétéroaryle et alkoxy, ces derniers radicaux hétéroaryle et alkoxy étant eux-mêmes éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et les radicaux hydroxyle, alkyle et alkoxy ;
    les radicaux aryle et hétéroaryle que peuvent représenter Ra, Rb et Re étant de plus éventuellement substitués par un ou plusieurs radicaux alkyle, eux-mêmes éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et les radicaux hydroxyle et alkoxy ;
    tous les radicaux cycloalkyle étant éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi un atome de fluor et les radicaux alkyle eux-mêmes éventuellement substitués par un ou plusieurs atomes de fluor ;
    tous les radicaux hétérocycloalkyle étant éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi un atome de fluor et les radicaux alkyle eux-mêmes éventuellement substitués par un ou plusieurs atomes de fluor ;
    tous les radicaux hétérocycloalkyle étant de plus éventuellement substitués par un radical CO2alk, lorsque cela est approprié sur un atome d'azote ;
    tous les radicaux alkyle (alk), alkylène et alkoxy ci-avant étant linéaires ou ramifiés et comportant au maximum 7 atomes de carbone,
    étant entendu qu'un ou plusieurs des atomes d'hydrogène desdits produits de formule (I) peuvent être des atomes de deutérium ;
    étant entendu que, lorsque p = 0 et l'un des radicaux R2 et R3 représente un radical alkyle et l'autre un radical alkyle substitué par un ou plusieurs atomes de fluor, alors R1 ne représente pas un radical phényle ou pyridyle selon la définition de a) ci-avant,
    lesdits produits de formule (I) se trouvant sous toute forme isomère racémique, énantiomère et diastéréoisomère possible, ainsi que les sels d'addition avec les acides inorganiques et organiques ou les bases inorganiques et organiques desdits produits de formule (I).
  2. Produits de formule (I) selon la Revendication 1, dans lesquels le résidu morpholine est choisi parmi les radicaux suivantes :
    Figure imgb0410
    Figure imgb0411
    Figure imgb0412
     les radicaux p, q, R1, R2, R3 et R4 prenant les valeurs indiquées dans la Revendication 1,
    lesdits produits de formule (I) se trouvant sous toute forme isomère racémique, énantiomère et diastéréoisomère possible, ainsi que les sels d'addition avec les acides inorganiques et organiques ou les bases inorganiques et organiques desdits produits de formule (I).
  3. Produits de formule (I) selon la Revendication 1 ou 2, dans lesquels p représente l'entier 0 et q représente l'entier 2, ou p représente l'entier 2 et q représente un entier 0 ;
    les radicaux R1, R2, R3 et R4 et le résidu morpholine prenant les valeurs indiquées dans la Revendication 1,
    lesdits produits de formule (I) se trouvant sous toute forme isomère racémique, énantiomère et diastéréoisomère possible, ainsi que les sels d'addition avec les acides inorganiques et organiques ou les bases inorganiques et organiques desdits produits de formule (I).
  4. Produits de formule (I) selon la Revendication 1 ou 2, dans lesquels p représente l'entier 0 et q représente l'entier 1, ou p représente l'entier 1 et q représente un entier 0 ;
    les radicaux R1, R2, R3 et R4 et le résidu morpholine prenant les valeurs indiquées dans la Revendication 1,
    lesdits produits de formule (I) se trouvant sous toute forme isomère racémique, énantiomère et diastéréoisomère possible, ainsi que les sels d'addition avec les acides inorganiques et organiques ou les bases inorganiques et organiques desdits produits de formule (I).
  5. Produits de formule (I) selon la Revendication 1 ou 2, dans lesquels :
    p et q représentent les entiers 0, 1 ou 2 de sorte que, si p = 0, alors q = 1 ou 2 et, si p = 1 ou 2, alors q = 0 ;
    R1 représente un radical phényle ou pyridyle éventuellement substitué par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et de chlore et les radicaux cycloalkyle, alkyle et alkoxy, ces derniers radicaux alkyle et alkoxy étant eux-mêmes éventuellement substitués par un ou plusieurs atomes de fluor ; un radical -(CH2)m-Ra; un radical -SO2-phényle éventuellement substitué par un radical alkyle ; un radical -CO-alkyle ; un radical alcényle ; ou un radical alkyle éventuellement substitué par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et les radicaux hydroxyle, cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle, oxétane, tétrahydrofurane, tétrahydropyrane, alkoxy, phényle et pyridine, ces trois derniers radicaux étant tous éventuellement substitués par un ou plusieurs atomes de fluor ;
    m représente l'entier 1 ou 2 ;
    Ra représente un radical -CO-Rb ; -C(cycloalkyl)=N-ORc ; CO2Rd ; -CONRxRy ; un radical -CO-cyclopropyle, - CO-cyclobutyle, -CO-cyclopentyle ou -CO-cyclohexyle, tous étant éventuellement substitués par un ou plusieurs radicaux alkyle ; un radical -CO-morpholine, -CO-pipéridyle, -CO-tétrahydrofurane, -CO-tétrahydropyrane ou -CO-pyrrolidine, tous étant éventuellement substitués par un ou plusieurs radicaux alkyle ou un radical CO2alk, lorsque cela est approprié sur un atome d'azote ; ou encore un radical phényle, pyridine, oxazole, isoxazole, oxadiazole, pyrazole, thiophène, thiazole, thiadiazole, pyridazine, benzimidazole, imidazopyridine ou triazole, tous étant éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes d'halogène fluor et chlore et les radicaux cycloalkyle, hétérocycloalkyle, hétéroaryle, alkyle et alkoxy, ces derniers radicaux hétéroaryle, alkyle et alkoxy étant eux-mêmes éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et les radicaux hydroxyle, alkyle et alkoxy ;
    Rb représente un radical alkyle, phényle, pyridyle, thiazole, isoxazole, oxazole ou oxadiazole, tous étant éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes d'halogène fluor et chlore et les radicaux cycloalkyle, hétérocycloalkyle, phényle, hétéroaryle, alkyle et alkoxy, ces derniers radicaux phényle, hétéroaryle, hétérocycloalkyle, alkyle et alkoxy étant eux-mêmes éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et les radicaux hydroxyle, alkyle et alkoxy ;
    Rc représente en particulier un atome d'hydrogène ou un radical alkyle ;
    Rd représente un radical alkyle ou cycloalkyle ;
    NRxRy sont tels que Rx et Ry, qui peuvent être identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle, alkoxy ou phényle ou forment ensemble un radical pipéridyle, morpholinyle, azétidine, oxa-azaspiro[3.3]heptane, isoxazolidine ou {1,2}oxazinane ;
    R2 et R3 sont tels que :
    soit R2 représente un atome d'hydrogène et R3 représente un radical trifluorométhyle CF3;
    soit R2 représente un radical méthyle et R3 représente le radical trifluorométhyle CF3;
    soit R2 et R3 représentent tous deux un radical méthyle ;
    R4 représente un atome d'hydrogène, de fluor ou de chlore, un radical méthyle ou un radical CN ;
    le résidu morpholine est choisi parmi les radicaux suivantes :
    Figure imgb0413
    Figure imgb0414
    Figure imgb0415
    lesdits produits de formule (I) se trouvant sous toute forme isomère racémique, énantiomère et diastéréoisomère possible, ainsi que les sels d'addition avec les acides inorganiques et organiques ou les bases inorganiques et organiques desdits produits de formule (I).
  6. Produits de formule (I) selon l'une quelconque des autres revendications, répondant aux formules suivantes :
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(3-méthyl-2-oxobutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(3-méthyl-2-oxobutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(2-fluoropyridin-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Cyclopropyl-2-oxoéthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxopropyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-((S)-2-hydroxypropyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((3R,5R)-3,5-Diméthylmorpholin-4-yl)-9-isoxazol-5-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(2-Chloropyridin-4-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-3-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Méthylisoxazol-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-oxazol-2-ylméthyl-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - [(S)-8-((R)-3-Méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétate d'éthyle
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxobutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(3-méthyl-[1,2,4]oxadiazol-5-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-[2-oxo-2-(tétrahydropyran-4-yl)éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(3-méthyl-[1,2,4]oxadiazol-5-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(2-méthoxyéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxobutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - 2-[(S)-7-Fluoro-8-((R)-3-méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]-N-méthoxy-N-méthylacétamide
    - (S)-9-(6-Fluoropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(2-Fluoropyridin-4-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxobutyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-9-(3-trifluorométhyl-[1,2,4]oxadiazol-5-ylméthyl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxobutyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-6-Fluoro-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-1-(2-Cyclopropyl-2-oxoéthyl)-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-9-(1-Difluorométhyl-1H-pyrazol-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-Isoxazol-3-ylméthyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chlorothiazol-5-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Chloropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-Isoxazol-5-ylméthyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Difluorométhyl-2H-pyrazol-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Fluoro-2-phényléthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-3-Fluoro-9-(2-méthoxypyridin-4-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chloropyridin-4-ylméthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-oxazol-2-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Cyclopropylpyridin-3-yl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-oxazol-4-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chloropyridin-4-yl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-isoxazol-5-ylméthyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-pyridin-3-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-[2-(2,2,2-trifluoroéthoxy)-éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(2-hydroxy-2-méthylpropyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-3-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(6-fluoropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Chloropyridin-3-ylméthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Difluorométhylpyridin-3-yl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylméthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-pyridin-4-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(5-fluoropyridin-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(5-fluoropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(2-fluoropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-[2-(3-fluoropyridin-2-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(3-Fluoropyridin-2-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(2-Méthoxypyridin-4-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(3-méthylisoxazol-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(6-Fluoropyridin-2-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-Imidazo[1,2-a]pyridin-2-ylméthyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(4-Chloropyridin-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Chloropyridin-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-3-pyridin-2-ylpropyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxo-2-thiazol-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-thiazol-4-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(5-Fluoropyridin-2-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - 3-Fluoro-8,8-diméthyl-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - 9-(2-Difluorométhyl-2H-pyrazol-3-ylméthyl)-8,8-diméthyl-2-((R)-3-méthylmorpholin-4-yl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - 3-Fluoro-9-isoxazol-3-ylméthyl-8,8-diméthyl-2-((R)-3-méthylmorpholin-4-yl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - 9-(2-Difluorométhyl-2H-pyrazol-3-ylméthyl)-3-fluoro-8,8-diméthyl-2-((R)-3-méthylmorpholin-4-yl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Fluorophényl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chloropyridin-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-oxazol-2-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-thiazol-4-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chloropyridin-4-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Méthoxypyridin-4-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-8-trifluorométhyl-9-(6-trifluorométhylpyridin-3-yl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[2-(2,2,2-trifluoroéthoxy)éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(6-méthylpyridin-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Hydroxy-2-méthylpropyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Isopropoxypyridin-3-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Chloropyridin-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-thiazol-5-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Cyclobutylpyridin-3-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Cyclopropylpyridin-4-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Méthoxyéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-oxazol-5-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Fluoropyridin-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2,5-Diméthyloxazol-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Fluoropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Chloropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(5-méthyl-[1,3,4]oxadiazol-2-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3,3-Diméthyl-2-oxobutyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Chlorothiophén-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-2-phényléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-((S)-2-Méthoxy-2-phényléthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Méthylisoxazol-5-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-oxazol-4-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(toluene-4-sulfonyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-Isoxazol-5-ylméthyl-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-Isoxazol-3-ylméthyl-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(6-Cyclopropylpyridin-3-yl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(2-Chloropyridin-4-yl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(2-Méthoxypyridin-4-yl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-oxazol-4-ylméthyl-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-oxazol-5-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(2-Chloropyridin-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(2-Hydroxy-2-méthylpropyl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(2-Isopropoxypyridin-4-yl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(6-Chloropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(6-Isopropoxypyridin-3-yl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-oxazol-5-ylméthyl-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(2-Cyclopropyl-2-oxoéthyl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-9-(2-méthoxypyridin-4-yl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(2-Cyclopropyl-2-oxoéthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(6-Difluorométhylpyridin-3-yl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(2-Chloropyridin-4-yl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(5-méthyl-[1,3,4]thiadiazol-2-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Difluorométhoxypyridin-3-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(4-méthyl-[1,2,3]thiadiazol-5-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-3-yléthyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(6-Difluorométhoxypyridin-3-yl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(3-méthyl-2-oxobutyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-oxazol-2-ylméthyl-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-(3-méthyl-2-oxobutyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-[2-oxo-2-(tétrahydropyran-4-yl)éthyl]-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-[2-oxo-2-(tétrahydropyran-4-yl)éthyl]-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-oxetan-3-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - 9-(6-Difluorométhylpyridin-3-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[1-(tétrahydrofuran-2-yl)méthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[1-(tétrahydrofuran-2-yl)méthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[1-(tétrahydropyran-2-yl)méthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[1-(tétrahydropyran-2-yl)méthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-8-trifluorométhyl-9-(5-trifluorométhyl-[1,3,4]oxadiazol-2-ylméthyl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-3-yléthyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Cyclopropyl-[1,3,4]oxadiazol-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(3-Méthylisoxazol-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-6-trifluorométhyl-9-(3-trifluorométhyl-[1,2,4]oxadiazol-5-ylméthyl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxopropyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-9-(3-méthylisoxazol-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-9-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylméthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxopropyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (R)-3-Fluoro-2-((R)-3-Méthylmorpholin-4-yl)-9-(3-méthyl-[1,2,4]oxadiazol-5-ylméthyl)-6-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-(3,3-Diméthylmorpholin-4-yl)-9-(2-oxo-2-phényléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Chlorothiophén-2-ylméthyl)-2-((3S,5R)-3,5-diméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one,
    - stéréoisomère unique
    - (S)-9-(5-Chlorothiophén-2-ylméthyl)-2-((3S,5S)-3,5-diméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((3S,5S)-3,5-Diméthylmorpholin-4-yl)-9-(2-oxo-2-phényléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Difluorométhyl-2H-pyrazol-3-ylméthyl)-2-((3R,5R)-3,5-diméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((3R,5R)-3,5-Diméthylmorpholin-4-yl)-9-(3-méthylisoxazol-5-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Chloropyridin-3-ylméthyl)-2-((3R,5R)-3,5-diméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chloropyridin-4-ylméthyl)-2-((3R,5R)-3,5-diméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((3R,5R)-3,5-Diméthylmorpholin-4-yl)-9-oxazol-2-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chloropyridin-4-yl)-2-((3R,5R)-3,5-diméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((3R,5R)-3,5-Diméthylmorpholin-4-yl)-9-pyridin-3-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3,5-Difluorophényl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Chlorothiophén-2-ylméthyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-phényléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-Isoxazol-5-ylméthyl-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chlorothiazol-5-ylméthyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Difluorométhyl-2H-pyrazol-3-ylméthyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(1-Difluorométhyl-1H-pyrazol-3-ylméthyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Chloropyridin-3-ylméthyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-Isoxazol-3-ylméthyl-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyridin-3-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-(2-Éthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one,
    - stéréoisomère unique
    - (S)-2-(2-Éthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-2-(2-Méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-2-(2-Méthylmorpholin-4-yl)-9-(2-oxo-2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-(3,5-Difluorophényl)-2-(3-hydroxyméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-(5-Chlorothiophén-2-ylméthyl)-2-(3-hydroxyméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-(5-Chlorothiophén-2-ylméthyl)-2-((S)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-Méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(2-oxo-2-pyridin-2-yléthyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-2-Méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(2-oxo-2-pyridin-3-yléthyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-1-(2-Chloropyridin-4-ylméthyl)-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-2-Méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-oxazol-5-ylméthyl-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-2-Méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-oxazol-4-ylméthyl-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-1-(2-Chloropyridin-4-ylméthyl)-6-fluoro-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-6-Fluoro-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(3-méthyl-2-oxobutyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-6-Fluoro-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-[2-oxo-2-(tétrahydropyran-4-yl)éthyl]-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-1-(2-Cyclopropyl-2-oxoéthyl)-6-fluoro-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-2-Méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(3-méthyl-2-oxobutyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-6-Fluoro-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(2-oxo-2-pyridin-3-yléthyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-2-Méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-[2-oxo-2-(tétrahydropyran-4-yl)éthyl]-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-9-Benzyl-2-(2-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-Benzyl-2-(2-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-Benzyl-2-(2-fluorométhylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-Benzyl-2-(2-fluorométhylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-Benzyl-2-(2-fluorométhylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - N-Méthoxy-N-méthyl-2-[(S)-8-((R)-3-méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétamide
    - N-Méthoxy-2-[(S)-8-((R)-3-méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétamide
    - (S)-2-((R)-3-méthylmorpholin-4-yl)-9-pyridin-4-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-6-Fluoro-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(2-oxo-2-pyridin-2-yléthyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-9-(2-Hydroxy-2-méthylpropyl)-8-méthyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Isopropyl-[1,2,4]oxadiazol-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(2-hydroxyéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-((S)-2-Hydroxypropyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-((S)-2-Méthoxy-2-phényléthyl)-2-(1R,5S)-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-6-Fluoro-2-méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(3-méthyl-[1,2,4]oxadiazol-5-ylméthyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-2-Méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(3-méthyl-[1,2,4]oxadiazol-5-ylméthyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-9-(2-Hydroxy-2-pyridin-3-yléthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-(2-Hydroxy-2-pyridin-3-yléthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-8-Méthyl-2-((R)-3-méthylmorpholin-4-yl)-9-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Hydroxy-2-pyridin-2-yléthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-(2-Hydroxy-2-pyridin-2-yléthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Difluorométhyl-2H-pyrazol-3-ylméthyl)-8-méthyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-Isoxazol-3-ylméthyl-8-méthyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-pyridin-4-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-pyridin-3-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-pyridin-2-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(4-Fluorophényl)éthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-pyridin-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Fluoropyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - N,N-Diméthyl-2-[(S)-8-((R)-3-méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétamide
    - N-Méthyl-2-[(S)-8-((R)-3-méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétamide
    - (S)-9-(6-Fluoropyridin-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Isopropoxypyridin-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Isopropyl-[1,2,4]oxadiazol-5-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-tert-Butyl-[1,2,4]oxadiazol-5-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Isopropoxypyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Isopropoxypyridin-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-thiazol-2-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-thiazol-2-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-2-pipéridin-1-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-méthylmorpholin-4-yl)-9-(2-morpholin-4-yl-2-oxoéthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-morpholin-4-yl-2-oxoéthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - 2-[(S)-8-((R)-3-Méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]-N-phénylacétamide
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxo-2-pipéridin-1-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-Acétyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-8-Méthyl-2-((R)-3-méthylmorpholin-4-yl)-9-oxazol-2-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-Méthyl-7-((R)-3-méthylmorpholin-4-yl)-1-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-2-trifluorométhyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
    - (S)-9-(2-Cyclopropyl-2-oxoéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-2-thiazol-2-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - [(S)-8-((R)-3-Méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétate de cyclopentyle
    - (S)-9-(2-Cyclopentyl-2-oxoéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[2-oxo-2-(tétrahydropyran-4-yl)éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(5-isopropyl-[1,2,4]oxadiazol-3-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylméthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(3-isopropyl-[1,2,4]oxadiazol-5-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylméthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-tert-Butyl-[1,2,4]oxadiazol-5-ylméthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-9-(3-trifluorométhyl-[1,2,4]oxadiazol-5-ylméthyl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-8-Méthyl-2-((R)-3-méthylmorpholin-4-yl)-9-(3-méthyl-2-oxobutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(1-Méthylcyclopentyl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - [(S)-8-((R)-3-Méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétate d'isopropyle
    - (S)-9-(3,3-Diméthyl-2-oxobutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxopropyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Fluoropyridin-4-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Cyclohexyl-2-oxoéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-pyridazin-4-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - [(S)-8-((R)-3-Méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétate de tert-butyle
    - 2-{2-[(S)-8-((R)-3-Méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétyl}pyrrolidine-1-carboxylate de tert-butyle
    - [(S)-8-((R)-3-Méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétate de méthyle
    - 2-[(S)-8-((R)-3-Méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétamide
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(4H-[1,2,4]triazol-3-ylméthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-oxo-2-pipéridin-4-yléthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Méthylbut-2-enyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Fluoro-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(3-Méthylisoxazol-4-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[2-oxo-2-(tétrahydrofuran-3-yl)éthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(5-Méthyl-[1,2,4]oxadiazol-3-ylméthyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Cyclopropyl-2-oxoéthyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Méthyl-2-oxobutyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Cyclopropyl-2-oxoéthyl)-3-fluoro-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(3-méthyl-2-oxobutyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(5-méthyl-[1,2,4]oxadiazol-3-ylméthyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(4-méthyl-2-oxopentyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((S)-3-Méthylmorpholin-4-yl)-9-(3-méthyl-2-oxobutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((S)-3-méthylmorpholin-4-yl)-9-(3-méthyl-2-oxobutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(5-méthyl-2-oxohexyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(4-méthyl-2-oxopentyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Éthyl-2-oxopentyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(3-Éthyl-2-oxopentyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - [(S)-7-Fluoro-8-((R)-3-méthylmorpholin-4-yl)-6-oxo-2-trifluorométhyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl]acétate de méthyle
    - (S)-9-sec-Butyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-sec-Butyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-(2-Hydroxy-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Hydroxy-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Méthoxy-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-9-(2-Méthoxy-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, stéréoisomère unique
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(5-méthyl-2-oxohexyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(3-méthyl-2-oxopentyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-8-trifluorométhyl-9-(3-trifluorométhyl-[1,2,4]oxadiazol-5-ylméthyl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-[2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-oxoéthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-[2-(5-méthylisoxazol-3-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Fluoro-2-phényléthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-isoxazol-3-ylméthyl-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Difluorométhyl-2H-pyrazol-3-ylméthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - 9-Isoxazol-3-ylméthyl-8,8-diméthyl-2-((R)-3-méthylmorpholin-4-yl)-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(3-méthylisoxazol-5-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Isopropoxyéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-pyridin-3-yl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(6-Cyclopropylpyridin-3-yl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-{2-[2-((R)-3-méthylmorpholin-4-yl)-pyridin-4-yl]-2-oxoéthyl}-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-{2-Cyclopropyl-2-[(Z)-hydroxyimino]éthyl}-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, isomère 1 de configuration indéterminée Z ou E
    - (S)-9-{2-Cyclopropyl-2-[(E)-hydroxyimino]éthyl}-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, isomère 2 de configuration indéterminée Z ou E
    - (S)-9-{2-Cyclopropyl-2-[(E)-méthoxyimino]éthyl}-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, isomère 1 de configuration indéterminée Z ou E
    - (S)-9-{2-Cyclopropyl-2-[(Z)-méthoxyimino]éthyl}-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, isomère 2 de configuration indéterminée Z ou E
    - (S)-9-(2-Cyclopropyloxetan-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 1 de configuration absolue indéterminée sur le carbone asymétriquue de la chaîne latérale
    - (S)-9-(2-Cyclopropyloxetan-2-ylméthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 2 de configuration absolue indéterminée sur le carbone asymétriquue de la chaîne latérale
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[2-(4-méthyltétrahydropyran-4-yl)-2-oxoéthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-[2-(5-Méthylisoxazol-3-yl)-2-oxoéthyl]-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Chlorothiazol-5-ylméthyl)-2-((3R,5R)-3,5-diméthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((3R,5R)-3,5-Diméthylmorpholin-4-yl)-9-isoxazol-3-ylméthyl-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(2-isoxazolidin-2-yl-2-oxoéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Hydroxyéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-[2-(6-oxa-1-azaspiro[3.3]hept-1-yl)-2-oxoéthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-(2-[1,2]oxazinan-2-yl-2-oxoéthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-(2-[1,2]oxazinan-2-yl-2-oxoéthyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Isoxazolidin-2-yl-2-oxoéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-2-(2-Méthylmorpholin-4-yl)-9-(3-méthyl-2-oxobutyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 1 de configuration absolue indéterminée sur le carbone asymétrique de la morpholine
    - (S)-9-(2-Cyclopropyl-2-oxoéthyl)-3-fluoro-2-((S)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Cyclopropyl-2-oxoéthyl)-3-fluoro-2-(2-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 1 de configuration absolue indéterminée sur le carbone asymétrique de la morpholine
    - (S)-9-(2-Fluoro-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 1 de configuration absolue indéterminée sur le carbone asymétrique de la chaîne 2-fluoro-3-méthylbutyle
    - (S)-9-(2-Fluoro-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 2 de configuration absolue indéterminée sur le carbone asymétrique de la chaîne 2-fluoro-3-méthylbutyle
    - (S)-9-(2-Cyclopropyl-2-fluoroéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 1 de configuration absolue indéterminée sur le carbone asymétrique de la chaîne 2-cyclopropyl-2-fluoroéthyle
    - (S)-9-(2-Cyclopropyl-2-fluoroéthyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 2 de configuration absolue indéterminée sur le carbone asymétrique de la chaîne 2-cyclopropyl-2-fluoroéthyle
    - (S)-8-Méthyl-2-((R)-3-méthylmorpholin-4-yl)-9-(2-oxopropyl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-3-Fluoro-9-(2-fluoro-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 1 de configuration absolue indéterminée sur le carbone asymétrique de la chaîne 2-fluoro-3-méthylbutyle
    - (S)-3-Fluoro-9-(2-fluoro-3-méthylbutyl)-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 2 de configuration absolue indéterminée sur le carbone asymétrique de la chaîne 2-fluoro-3-méthylbutyle
    - (S)-2-((R)-3-Méthylmorpholin-4-yl)-9-[2-(1-oxa-6-azaspiro[3.3]hept-6-yl)-2-oxoéthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    - (S)-9-(2-Cyclopropyl-2-fluoroéthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 1 de configuration absolue indéterminée sur le carbone asymétrique de la chaîne 2-cyclopropyl-2-fluoroéthyle
    - (S)-9-(2-Cyclopropyl-2-fluoroéthyl)-3-fluoro-2-((R)-3-méthylmorpholin-4-yl)-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one, diastéréoisomère 2 de configuration absolue indéterminée sur le carbone asymétrique de la chaîne 2-cyclopropyl-2-fluoroéthyle
    - (S)-3-Fluoro-2-((R)-3-méthylmorpholin-4-yl)-9-[2-(1-oxa-6-azaspiro[3.3]hept-6-yl)-2-oxoéthyl]-8-trifluorométhyl-6,7,8,9-tétrahydropyrimido[1,2-a]pyrimidin-4-one
    ainsi que les sels d'addition avec les acides inorganiques et organiques ainsi qu'avec les bases inorganiques et organiques desdits produits de formule (I).
  7. Procédé de synthèse des produits de formule (I) selon l'une quelconque des autres revendications, selon le schéma 2 comme défini ci-après :
    Figure imgb0416
     dans lequel les substituants p, q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 et alkyle prennent les valeurs indiquées pour les produits de formule (I) sous n'importe laquelle des Revendications 1 à 5, n est égal à 0 ou 1 et PG représente un groupement protecteur pour une amine.
  8. Produit de formule (I) selon l'une quelconque des Revendications 1 à 6, ainsi que les sels d'addition pharmaceutiquement acceptables avec des acides inorganiques et organiques ou avec des bases inorganiques et organiques desdits produits de formule (I), pour utilisation comme médicament.
  9. Produit de formule (I) selon la Revendication 6, ainsi que les sels d'addition pharmaceutiquement acceptables avec des acides inorganiques et organiques ou avec des bases inorganiques et organiques desdits produits de formule (I), pour utilisation comme médicament.
  10. Compositions pharmaceutiques contenant au titre de principe actif au moins l'un des produits de formule (I) selon l'une quelconque des Revendications 1 à 6, ou l'un des sels pharmaceutiquement acceptables de ce produit ainsi qu'un vecteur pharmaceutiquement acceptable.
  11. Produits de formule (I) selon l'une quelconque des Revendications 1 à 6, pour utilisation dans le traitement prophylactique ou thérapeutique d'une maladie choisie dans le groupe suivant : troubles de prolifération des vaisseaux sanguins, troubles fibrotiques, troubles de prolifération cellulaire mésangiale, troubles métaboliques, allergies, asthme, thrombose, maladies du système nerveux, rétinopathie, psoriasis, polyarthrite rhumatoïde, diabète, dégénérescence musculaire et cancers.
  12. Produits de formule (I) pour utilisation selon la Revendication 11, pour utilisation dans le traitement des cancers.
  13. Produits de formule (I) pour utilisation selon l'une quelconque des Revendications 11 ou 12, pour utilisation dans le traitement des tumeurs solides ou liquides.
  14. Produits de formule (I) pour utilisation selon l'une quelconque des Revendications 11 ou 13, pour utilisation dans le traitement des cancers résistant aux agents cytotoxiques.
  15. Produits de formule (I) pour utilisation selon l'une quelconque des Revendications 11 à 14, pour utilisation dans le traitement de tumeurs primaires et/ou de métastases, en particulier dans les cancers de l'estomac, du foie, du rein, de l'ovaire, du côlon, de la prostate et du poumon (non à petites cellules et à petites cellules), glioblastomes, thyroïde, cancers de la vessie et du sein, dans les mélanomes, dans les tumeurs lymphoïdes ou myéloïdes hématopoïétiques, dans les sarcomes, dans les cancers du cerveau, du larynx et du système lymphatique, les cancers de l'os et du pancréas, et dans les hamartomes.
  16. Produits de formule (I) pour utilisation selon l'une quelconque des Revendications 11 ou 15, pour utilisation en chimiothérapie anticancéreuse.
  17. Produits de formule (I) pour utilisation selon l'une quelconque des Revendications 11 ou 16, pour utilisation en chimiothérapie anticancéreuse seuls ou en combinaison.
  18. Produits de formule (I) pour utilisation selon la Revendication 11, pour utilisation dans le traitement des maladies lysosomales comme la glycogénose de type 2 (ou maladie de Pompe) ou la maladie de Danon.
  19. Produits de formule (I) pour utilisation selon la Revendication 11, pour utilisation dans le traitement de myopathies myotubulaires liées à l'X et la maladie de Charcot-Marie-Tooth.
  20. Au titre de nouveaux produits industriels, les produits de départ ou les intermédiaires de synthèse selon la Revendication 7 comme suit :
    - de formule P :
    Figure imgb0417
    dans laquelle p et q représentent les entiers 0, 1 ou 2 de sorte que, si p = 0, alors q = 1 ou 2 et, si p = 1 ou 2, alors q = 0 ;
    R2 et R3, qui peuvent être identiques ou différents, sont choisis parmi un atome d'hydrogène et un radical alkyle éventuellement substitué par un ou plusieurs atomes de fluor, étant entendu que R2 et R3 ne représentent pas tous deux CF3 et R2 et R3 ne représentent pas tous deux un atome d'hydrogène ; ou R2 et R3 forment, avec l'atome de carbone auquel ils sont liés, un radical cyclique comportant entre 3 et 6 chaînons ainsi qu'éventuellement un ou plusieurs autres hétéroatomes choisis parmi 0, S et -NRz, ce radical cyclique étant éventuellement substitué par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes d'halogène et les radicaux oxo, Rz, -ORz et -NRzRz' ; Rz et Rz', qui peuvent être identiques ou différents, représentant un atome d'hydrogène ou un radical alkyle, cycloalkyle ou hétérocycloalkyle ;
    R4 représente un atome d'hydrogène, de fluor ou de chlore, un radical méthyle ou un radical CN ;
    le résidu morpholine est substitué par les radicaux R5 à R12, qui peuvent être identiques ou différents, choisis parmi un atome d'hydrogène et des radicaux méthyle et éthyle éventuellement substitués par un atome de fluor ou un radical hydroxyle, étant entendu qu'au moins l'un des radicaux R5 à R12 ne représente pas un atome d'hydrogène ou ce résidu morpholine comporte un pont défini de la façon suivante : R7 ou R8 peut former un pont éthylène avec R9 ou R10, ou R7 ou R8 peut former un pont méthylène de configuration absolue R,R avec R11 ou R12, ou encore R5 ou R6 peut former un pont méthylène de configuration absolue R,R avec R9 ou R10 de sorte à obtenir les radicaux suivants :
    Figure imgb0418
     et l'isomère de configuration R,R
    Figure imgb0419
    les radicaux aryle et hétéroaryle que peuvent représenter Ra, Rb et Re, ainsi que les radicaux alkyle que peuvent représenter Rb et Re étant éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes d'halogène et les radicaux cycloalkyle, hétérocycloalkyle, hétéroaryle et alkoxy, ces derniers radicaux hétéroaryle et alkoxy étant eux-mêmes éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et les radicaux hydroxyle, alkyle et alkoxy ;
    les radicaux aryle et hétéroaryle que peuvent représenter Ra, Rb et Re étant de plus éventuellement substitués par un ou plusieurs radicaux alkyle, eux-mêmes éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi les atomes de fluor et les radicaux hydroxyle et alkoxy ;
    tous les radicaux cycloalkyle étant éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi un atome de fluor et les radicaux alkyle eux-mêmes éventuellement substitués par un ou plusieurs atomes de fluor ;
    tous les radicaux hétérocycloalkyle étant éventuellement substitués par un ou plusieurs radicaux, qui peuvent être identiques ou différents, choisis parmi un atome de fluor et les radicaux alkyle eux-mêmes éventuellement substitués par un ou plusieurs atomes de fluor ;
    tous les radicaux hétérocycloalkyle étant de plus éventuellement substitués par un radical CO2alk, lorsque cela est approprié sur un atome d'azote ;
    tous les radicaux alkyle (alk) , alkylène et alkoxy ci-avant étant linéaires ou ramifiés et comportant au maximum 7 atomes de carbone,
    étant entendu qu'un ou plusieurs des atomes d'hydrogène desdits produits de formule (I) peuvent être des atomes de deutérium ;
EP13773341.6A 2012-06-22 2013-06-21 Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one et this1,2,4-tetrahydropyrimido {1,2-a}pyrimidin-6-one comprenant une morpholine substituee, leurs preparation et utilisation pharmaceutique Active EP2864295B1 (fr)

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PCT/IB2013/055099 WO2013190510A2 (fr) 2012-06-22 2013-06-21 Nouveaux dérivés de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one et de 1,2,3,4-tétrahydropyrimido{1,2-a}pyrimidin-6-one comprenant une morpholine substituée, leur procédé de préparation et leur utilisation pharmaceutique

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FR2992314B1 (fr) 2015-10-16
FR2992314A1 (fr) 2013-12-27
CN104603113B (zh) 2020-01-21
ES2662803T3 (es) 2018-04-09
MX350682B (es) 2017-09-13
PT2864295T (pt) 2018-03-15
TW201402577A (zh) 2014-01-16
US10253043B2 (en) 2019-04-09
AU2013278875B2 (en) 2017-06-15
US20150148328A1 (en) 2015-05-28
DK2864295T3 (en) 2018-03-19
WO2013190510A3 (fr) 2014-03-06
JP2015525236A (ja) 2015-09-03
CA2877089A1 (fr) 2013-12-27
EP2864295A2 (fr) 2015-04-29
BR112014031845A2 (pt) 2017-06-27
RU2015101798A (ru) 2016-08-10
AU2013278875A1 (en) 2015-01-22
IN2014KN02940A (fr) 2015-05-08
US20190292205A1 (en) 2019-09-26
IL236170A0 (en) 2015-02-01
US11739100B2 (en) 2023-08-29
KR20150023799A (ko) 2015-03-05
SG11201408207TA (en) 2015-01-29
WO2013190510A2 (fr) 2013-12-27
MX2014015949A (es) 2015-07-17
CN104603113A (zh) 2015-05-06
PL2864295T3 (pl) 2018-06-29
AR091498A1 (es) 2015-02-11
IL236170A (en) 2017-03-30

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